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Table 1 Metabolic signaling regulators that improve CAR-T cell destiny and reverse exhaustion

From: Rewiring mitochondrial metabolism to counteract exhaustion of CAR-T cells

Target Compounds FDA approval Model Outcome References
PI3K LY294002
IC87114
No 1. MOLM-13-CD19 cell line
2. NSG mice AML model
Increasing TN and TCM populations of CD33 CAR-T in vivo
Improving CAR-T cell persistence and reducing tumor burden in vivo
[119]
PDK
Glycolysis
Dichloroacetate Yes 1. Hepatocellular carcinoma (HCC) cell lines
2. HCC-bearing mice model
Increasing TN and TCM percentages
Reducing lactate-mediated immunosuppression
[168]
mTOR Rapamycin Yes Acute lymphocytic choriomeningitis virus infection mice model Enhancing the formation of memory CD8 T cells during the naïve to effector T cell differentiation phase and the effector to memory transition phase in vivo
Improving the functional qualities of the memory CD8 T cells in vivo
[117]
Akt A-443654 No LCMV-infected mice model Rescuing short-lived effector cells from deletion due to sustained Akt activation
Enhancing P14 CD8 TEM cells in vivo
[118]
Akt Akti-1/2 No 1. CD19 + lymphoid leukemic cell line
2. CD19 + tumor-bearing immunodeficient mice model
Preventing CAR-T cell differentiation
Increasing cytokine production and cytotoxicity
Exhibiting greater anti-tumor efficacy and expansion in vivo
[124]
BATF
c-Myc
JQ1 No 1. K562 cell line, CD19 + leukemia cell line NALM-6,melanoma cell line A375
2. ALL or melanoma-bearing NSG mice model
Promoting the maintenance of TSCM and TCM phenotypes, persistence and antitumor effects of CAR-T cells in vivo [169]
PI3Kγ
PI3Kδ
IPI-549
CAL-101
TGR-1202
No 1. B16F10 (H-2b) melanoma cell line
2. K562-mesothelinexpressing cell line
3. pmel-1 TCR-transgenic mice model
Sole blockade of PI3Kγ or PI3Kδ, but not dual inhibition, induces a naive/stem memory-like profile and enhances in vivo antitumor immunity of infused CD8+ T cells
PI3Kδ inhibition improves cytotoxicity of Meso-CAR T cells
[121]
PI3Kδ Idelalisib Yes 1. PBMCs fromconsenting DLBCL patients and healthy controls
2. NSG mice model
3. B6 SJL mice lymphoma model
Enhancing the expansion and functionality of CAR-T cells in vitro
Enhancing DLBCL patient T cells persistence in vivo
Enhancing anti-tumor activity of OT-T cells in a murine lymphoma model
[120]
PGC-1α
PPAR-α
Bezafibrate
Fenofibrate
Yes 1. Melanoma mice model
2. Skin sarcoma BALB/c mice model
Promoting FAO
Improving CD8+ TIL functions
Synergizing with PD-1 blockade
[133, 136, 170]